Introduction

A gallium scan is a study that uses intravenously injectable isotopes of gallium to produce nuclear medicine images. Gallium was one of the first radioisotopes used for diagnostic nuclear medicine. Gallium, discovered in 1875 by Paul-Émile Lecoq de Boisbaudran, was first considered for diagnostic and therapeutic medical use in the 1940s by the research of H. C. Dudley and his co-workers. Gallium scans were initially used for localizing tumors and abscesses. Commercially available radiopharmaceuticals gallium-67 (67Ga) and gallium-68 (68Ga) are widely used. Although gallium-72 proved less useful for medical use, gallium-67, produced by proton bombarded zinc, and particularly gallium-68, produced by generator accelerating of germanium-68 (68Ge), emerged as solid contenders after measurement instrumentation became more advanced. Initially, gallium-67 was unexpectedly found to highlight Hodgkin’s lymphoma, although it was intended for osseous cancer. It was later realized that the isotope could be used for a broader range of malignancies and inflammatory processes.[1] Historically, gallium-67 scans were used to diagnose many diseases, including bone infections, cancers (especially lymphomas), fevers of unknown origin, non-specific inflammation, and intra-abdominal abscesses. It was also used to evaluate inflammatory disease of the lungs like sarcoidosis, interstitial pneumonitis, pulmonary tuberculosis, and pulmonary fibrosis.[2] Gallium-67 is used with single-photon emission computed tomography (SPECT), while gallium-68 is used with positron emission tomography (PET).

Gallium is trivalent metal and treated similarly to ferric iron in the body. Gallium-67 is relatively insoluble at normal pH and requires substances like citrate ions to form a complex to dissolve once in the body. Roughly 75% of the administered dose remains in the body after 48-72 hours and distributes evenly in soft tissues, liver, and bone. Around 90% of 67Ga is bound to transferrin in the blood plasma. Subsequently, it dissociates at low pH (exudate, or tumor site) and binds to lactoferrin due to vascular flow increased in the area. White blood cells may bind and transport 67Ga as well. Siderophores produced by bacteria have a good affinity for 67Ga and can form a complex to be taken up by the bacteria. It is also thought that bacteria have direct uptake of 67Ga via facilitated diffusion and nonspecific binding sites.[3] 

Gallium-68 (68Ga) is a positron-emitting isotope with a half-life of 68 minutes. It can be generated from germanium-68 or zinc-68. It can be used for the inherent properties in the radiometal itself or the chelated agent's chemical properties (most commonly a somatostatin analog). It is often attached to a specific chelating agent to be used as a tracer (e.g., DOTA-octreotate, also known as DOTATATE). The agent keeps gallium stably bound and free to distribute while binding to a specific receptor molecule. DOTATATE, DOTATOC, and DOTANOC are also referred to as GaTate, GaToc, and GaNoc, respectively. Bifunctional chelating is used to bind the metal (68Ga3+ ion) to a complex. The complex should have a high affinity with gallium for in vivo stability, while the targeting biomolecule (ex. drug, peptide, or antibody) in the complex is free to bind to a specific site and concentrate there. Essentially, gallium is paired with a compound that binds to a target tissue site. The complex is injected intravenously and is imaged with a PET detector at specific times depending on the desired target site uptake, but usually after one hour. In the case of GaTate, affinity is highest to the somatostatin receptor (SSTR) subtype 2. This leads to intense uptake in the spleen, adrenal glands, kidneys (not due to SSTR), and pituitary, with moderate intensity in the liver (not due to SSTR), thyroid, and saliva glands. There is also uptake in other areas such as the pancreas, bone, brain, and lymph nodes.[4] GaToc has a high affinity to SSTR subtype 5, and GaNoc has a high affinity to SSTR subtypes 3 and 5. A homogenous uptake is physiologic, while intense heterogeneous, irregular focal uptake is worrying. The PET scan is usually done with a whole-body computed tomographic (CT) scan for detailed anatomical mapping, referred to as a PET/CT scan.

The renewed interest in gallium is due to its widespread availability as it is generator-produced and has a short half-life. Using gallium, on-site labeling, and radiopharmaceutical use can be done without a cyclotron nearby or delivering the product. The radiolabel paired has varying sensitivity and specificity inherent to the tissue or receptor properties.[5] DOTATATE has recently been given orphan drug status, and that also has renewed some of the interest in gallium-68.

Gallium-67 is a gamma-emitting isotope with a half-life of 3.26 days that was used for imaging many pathologies, although now, fluorine-18 (18F) fluoro-deoxyglucose (FDG) (18F-FDG) has mostly replaced it. Both isotopes require a high-energy cyclotron for production and for doses to be individually purchased; therefore, they are not always available. 18F-FDG, a nonspecific metabolic indicator using glucose metabolism, has mostly replaced gallium-67, but recently there have been new developments in gallium’s utility, now as a gallium-68 labeled radiotracers. This evolution includes a shorter half-life, on-site generation, somatostatin receptor, prostate (68Ga-PSMA-11 PET/MR) tracers, and other cancer diagnoses, including boney and soft tissue metastasis.[6][7] Gallium-67 (67Ga) is still used for imaging inflammation and granulomatous reactions. It produces low resolution and image quality and has a high radiation burden to patients due to its longer half-life. Imaging takes place at least two days after injection due to this long half-life. Gallium-67 is commonly bonded with citrate or nitrate (both dissociate in the blood when injected, leaving the gallium ion, 67Ga3+). Although WBC SPECT imaging has mostly replaced gallium-67 for infection imaging, there are still specific circumstances for it to be used. Examples include to rule out false negatives on spinal infections, immunocompromised patients, and chronic infections.[8]

Gallium-68 is typically created by a 68Ge/68Ga generator. This process has an advantage over 18F-FDG, as 68Ga does not require a nearby cyclotron, and the parent isotope 68Ge has a half-life of 271 days. 68Ge is usually made from proton bombardment of 69Ga.[9] 68Ge decays through electron capture. 68Ga mostly decays through positron emission (yields 89%) with a mean MeV of 0.89 and maximum energy of 1.9MeV.[10] That is higher energy than 18F (with positron yield 96.7%), which is 0.25 MeV and max 0.63MeV. Since lower positron emission yields and higher endpoint energy emission leads to lower resolution in PET scans, this causes Gallium to have a theoretically lower resolution on imaging. Gallium has lower sensitivity and inferior spatial resolution than 18F, but gallium has a high clinical image contrast when labeled, making lesion detection easier.[10] Moreover, both radionuclides produce high-quality imaging as long as a 3mm detection scanner is used.[11] Imaging can occur in approximately one hour due to the short half-life. The 68Ga3+ cation allows it to join various molecules using oxygen, nitrogen, and sulfur as atom donors. Due to increased gallium-68 demands, it can also be created by a medical cyclotron.[12] Originally 68Ga was paired with ligands such as EDTA (ethylenediaminetetraacetic acid) derivatives, and years later, developed pairing with DTPA (diethylenetriaminepentaacetic acid) or DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-based derivatives. This allowed 68Ga-DOTA-octreotate to become an alternative to Indium-111-DTPA-octreoscan.[13] 68Ga can be paired with many molecules, including citrate, which gives it the same site affinities as 67Ga, but lower half-life. There are currently trials pairing 68Ga with antimicrobials such as ciprofloxacin and DOTA-depsidomycin.[8]

Procedures

Before the initiation of the procedure, the medical team reviews the critical medical information of the patient. The patient is informed in detail of the procedure, and with the agreement, the study begins. Food and liquid restrictions are not required, but the patient should be well hydrated with regular bowel movements. The 68Ga-DOTA-conjugates are eliminated by the kidneys, while the kidneys and bowel eliminate 67Ga-citrate.

The radiopharmaceutical agent is delivered intravenously to the patient with no interacting substances. Activity administered should be above 100MBq, but can range from 100-200MBq. For example, 67Ga should be 185MBq, 5mCi in adults, and 3.7-7.4MBq/kg, 0.1 to 0.2mCi/kg in children.[14] The time before scanning depends on the compound used. Usually, between 45 minutes to 90 minutes for 68Ga bound compounds, it varies depending on the desired target organ uptake and the compound used. Images for 67Ga are taken 48 hours after administration, then 72 hours for delayed images, and even up to 5 days after to help differentiate lesions.

The patient should void their bladder before scanning to remove unbound radioactive compounds and reduce image noise, allowing better imaging of the area and decrease radiation exposure to the urinary tract. Metals on the body are also removed during the procedure due to their potential for imaging interference. The patient's whole body is imaged with typical imaging times of approximately 30 minutes to 60 minutes per view, but it depends on the size being imaged. The patient should remain still and quiet during imaging to reduce motion artifacts. The patient is discharged after the scan is completed when the radiation emission levels are safe and reviewed by the physician.

The patient should avoid contact with pregnant women and infants for as long as the physician advises. A waiting period of 7 half-lives allows for less than 1% of original radiation to persist. This guide can also be used as a general safety rule during breastfeeding. The image is reported in detail by the nuclear radiologist using all the patient's acquired relevant history.

Indications

Neuroendocrine tumors (68Ga-DOTA-TATE, DOTA-NOC, DOTA-TOC): 68Ga conjugates should be used as the preferred functional imaging modality for the evaluation of neuroendocrine tumors (NETs) for all histological grades.[15][16] Ideally, it is used alone for histological well-differentiated/low-grade tumors; however, if the tumor is not well-differentiated, it should be used in conjunction with the 18F-FDG PET/CT scan.[16][17][18][19][20] NETs include pituitary adenoma, pancreatic islet cell tumors, carcinoid, pheochromocytoma, paraganglioma, medullary thyroid cancer, and small cell lung carcinoma.[5]

Prostate cancer: (68Ga-labeled inhibitors of prostate-specific membrane antigen (68Ga-PSMA), 68Ga-bombesin/68Ga-RM2, 68Ga-DOTATOC)[17][20][21]

67Ga-citrate is mainly used for lymphomas (Hodgkin’s and non-Hodgkin’s) and fever of unknown origin. Although more effective agents exist, it can still be used for lung cancer, lung inflammatory diseases, bone infections, melanoma, germ cell tumors, hepatocellular carcinoma, neuroblastoma, multiple myeloma, sarcoma, head and neck tumors. 67Ga is currently only used for spinal infections when FDG cannot be performed.[22]

Emerging indications for 68Ga:

• 68Ga-DOTATATE may play a role in other somatostatin receptor tumors such as renal cell cancer, breast cancer, prostate cancer, malignant lymphoma, hepatocellular cancer, medulloblastoma, neuroblastoma, sarcoma, and gastric cancer.[23][24]
• Meningioma (68-DOTATATE)[17][24][25]
• Osteomyelitis and discitis (68Ga-citrate)[26][27]
• Breast cancer (68Ga-bombesin, 68Ga-ABY-002)[28]
• Melanoma (68Ga-melanocortin)[29][30]
• Tumor therapy response (68Ga binding to DOTA-related analogs such as P-glycoprotein, cholecystokinin, neurotensin, and substance P)[17]
• Pathologic angiogenic processes (68Ga-RGB, arginine, glycine, aspartic acid peptides)[17]
• Alzheimer’s disease (68Ga-DOTA-C3-BF)[31]
• Cerebral amyloid angiopathy[32]
• Pathology with activated macrophages (68Ga-deferoxamine-folate). Crohn’s disease, rheumatoid arthritis, systemic lupus erythematosus, diabetes, vasculitis, sarcoidosis, atherosclerosis.[33]
• Cardiac imaging (68Ga-NOTA/DOTA-RGD, 68Ga-DOTAVAP-PEG-P). Myocarditis, atherosclerotic plaques, and post-myocardial infarction inflammation[17]
• Respiratory imaging (68Ga-DOTA-NOC) in pulmonary fibrosis and (68Ga-DOTATATE) in sarcoidosis[8][17]
• Inflammatory bowel disease (68Ga-Citrate)[8]
• Colorectal, esophagus, breast, lung, pancreatic, head and neck cancers (68Ga-fibroblast-activation-protein inhibitors) (68Ga-FAPI)[34]
• Pulmonary embolism (68Ga-carbon nanoparticles and 68Ga-macro-aggregated albumin)[35][36]

Interfering Factors

Blood transfusions and hemolysis can interfere with the body's iron distribution; thus, it is not recommended to have a gallium-citrate scan after a recent transfusion due to uptake anomalies. Depending on the conjugated molecule for 68Ga scans, there could be metabolic interference from various substances. For example, therapeutic somatostatin analogs may interfere with 68Ga-DOTATATE scans, so if possible, short-acting somatostatin analogs should be stopped 24 hours before the scan.

Motion artifact may be a source of error. Other sources of error include but are not limited to: misinterpreting physiological uptake areas, anatomical uptake variation, clothing and skin contamination with urine, recent procedures or trauma, recent or current chemotherapy, medication-related uptake changes (ex. somatostatin analogs decreasing uptake of 68Ga-DOTATATE, or granulocyte-colony stimulating factor increasing bone uptake of gallium), and rarely instrumentation calibration error (ex. PET/CT superimposition error).[25]

Complications

Some rare allergic reactions can occur and include but are not limited to erythema, rash, pruritis, nausea, vomit, tachycardia, dizziness, and syncope.[37][38]

There are no contraindications to the gallium scan, but precautions should be taken to avoid complications:

• During pregnancy, whether suspected or confirmed, a clinical decision of risks vs. benefit must be made.
• Breastfeeding should be discontinued, with milk extraction post-procedure and breastfeeding resumed when the radiation dose to the child would be less than 1mSv. It is recommended to wait 8 hours after the 68Ga scan before milk extraction, and breastfeeding should resume.
• Pediatric cases should be carefully evaluated to avoid radiation exposure unless there is a clear suspicion of malignancy.
• It may be beneficial to cease somatostatin analog therapy before a DOTA scan.

Patient Safety and Education

Radioactive gallium isotopes are inherently hazardous to one's health. Both healthcare staff and patients must be aware of the dangers and take reasonable precautions. The patient should be informed that the risk of radiation exposure is less than the scan's benefits and should understand why the scan is indicated. They should also understand others' risks when they emit radiation, especially to children, during lactation and pregnancy. The patient should be encouraged to ask questions about safety concerns.

Organs have different uptake of the isotope, and there are individual variations as well. For example, a patient post-splenectomy would have higher uptake in other organs. The average effective whole-body dose of 67Ga is 18.5mSv, while 68Ga-DOTATATE is 3.0mSv.[39][40] With a comparatively significant reduction in effective dose, 68Ga is starting to prove to have lower exposure adverse outcomes.[41]

Clinical Significance

Until recently, gallium scans can detect many pathologies and have been phased out due to newer developments (ex. 18F-FDG). Gallium was limited to detecting cancer and inflammatory processes only, but now the gallium redux is expanding to detect all kinds of pathology with gallium-68 as a radiotracer. Gallium scans are adjuncts for diagnosis, although some conjugates have specific receptors. Gallium distributes in the body according to the conjugate used. If citrate is used, gallium's natural properties allow the body to metabolize it like ferric iron.

If gallium is chelated with other molecules (ex. DOTATATE), it distributes in the body according to the receptor's affinity to that molecule. An abnormal accumulation of gallium implies a localization of underlying pathology, either tumor or inflammation with citrate as a conjugate or specific pathologies (ex. NETs) depending on the conjugate molecule.

68Ga can be conjugated with various molecules to help diagnose multiple pathologies. Currently, it is primarily used for cancer detection (NETs and prostate cancer). It can be used in the detection, staging, post-treatment response, and surveillance of cancer. It can be used alone but is usually used complementary to other imaging methods (ex. 18F-FDG PET, CT, MRI, etc.) for more detailed anatomy and specificity. Further developments and research may allow gallium-68 scans to adequately diagnose pulmonary embolisms, cardiac pathologies, respiratory pathologies, Alzheimer's disease, bone infections, and other cancers.

67Ga-citrate is primarily used to help diagnose lymphomas (Hodgkin's and non-Hodgkin's, especially for restaging), fever of unknown origin. It may be used in certain cancers (ex. bronchogenic carcinoma), although 18F-FDG has superseded it.